Preclinical evaluation of polymer-bound doxorubicin

Duncan, Ruth; Seymour, Len; O'Hare, K.B.; Flanagan, Pauline A.; Wedge, S. R.; Hume, Isabella C.; Ulbrich, Karel; Strohalm, J.; Šubr, Vladimír; Spreafico, F.; Grandi, Maria; Ripamonti, Marina; Farao, M.; Suarato, Antonino

doi:10.1016/0168-3659(92)90088-9

Cited by 179 publications

(95 citation statements)

References 27 publications

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“…This agent, FCE28068 (known as 'PK1'), consists of the anthracycline doxorubicin linked to copolymers based on N-(2-hydroxypropyl)methacrylamide via a tetrapeptide spacer designed for cleavage by lysosomal cathepsins (11). Following endocytic entry into tumour cells the spacer is cleaved, allowing intracellular release of active doxorubicin (3,12,13). In the phase I trial, FCE28068 was found to mediate ~5-fold decreased toxicity than the equivalent dose of free doxorubicin, with the maximum tolerated dose identified as 320 mg/m 2 .…”

Section: Introductionmentioning

confidence: 99%

Phase II studies of polymer-doxorubicin (PK1, FCE28068) in the treatment of breast, lung and colorectal cancer

Seymour¹

2009

Int J Oncol

266

124

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Abstract. Phase I studies of [N-(2-hydroxypropyl)methacrylamide] (HPMA) copolymer-doxorubicin previously showed signs of activity coupled with 5-fold decreased anthracycline toxicity in chemotherapy-refractory patients. Here we report phase II studies using a similar material (FCE28068) in patients with breast (n=17), non-small cell lung (NSCLC, n=29) and colorectal (n=16) cancer. Up to 8 courses of PK1 (280 mg/m 2 doxorubicin-equivalent) were given i.v., together with 123 Ilabelled imaging analogue. Toxicities were tolerable, with grade 3 neutropenia more prominent in patients with breast cancer (4/17, 23.5% compared with 5/62, 8.1% overall). Of 14 evaluable patients with breast cancer 3 had partial responses (PR), all anthracycline-naïve patients. In 26 evaluable patients with NSCLC, 3 chemotherapy-naïve patients had PR. In contrast, none of the 16 evaluable patients with colorectal cancer responded. Imaging of 16 patients (5 with breast cancer, 6 NSCLC, 5 colorectal cancer) showed obvious tumour accumulation in 2 metastatic breast cancers, although unfortunately no images were obtained from patients who responded. These results show 6/62 PR with limited side effects, supporting the concept that polymer-bound therapeutics can have modified and improved anticancer activities and suggesting the approach should be explored further for breast cancer and NSCLC.

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Section: Introductionmentioning

confidence: 99%

Phase II studies of polymer-doxorubicin (PK1, FCE28068) in the treatment of breast, lung and colorectal cancer

Seymour¹

2009

Int J Oncol

266

124

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“…In particular, Lysosomotropic polymerdrug conjugates, block copolymer micelles and PEG-protein conjugates came into consideration due to the revolutionary work of De Duve et al (1974), Ringsdorf (1975), Abuchowski et al (1977) and others. Further, since 1980s onwards Duncan and Kopecek have initiated research on the use of synthetic polymers like N-2-hydroxypropyl methacrylamide (HPMA), Poly ethyleneglycol (PEG) and Poly N-isopropylacrylamide (Poly-NIPAAm) for drug delivery purposes (Duncan & Kopecek, 1984;Duncan, 1992Duncan, , 2009Duncan et al, 1992). The first polymer-drug conjugate, HPMA-Doxorubicin conjugate, has now entered Phase II clinical trials.…”

Section: Anticancer Drug Targeting Applications Of Elpsmentioning

confidence: 99%

Elastin-like polypeptides and their applications in anticancer drug delivery systems: a review

Saxena

Nanjan

2013

Drug Delivery

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Elastin-like polypeptides (ELPs) are large molecular weight biopolymers. They have been widely studied as macromolecular carriers for targeted delivery of drugs. The aim of the present article is to review the available information on ELPs (including our recent investigations), their properties, drug delivery applications to tumor sites and future perspectives. This review also provides information on the use of short synthetic ELPs for making ELP-drug conjugates, for targeted delivery of anticancer drugs. In the present review we also focus on the point that short ELPs can also be used for targeting anticancer drugs to tumor sites as they behave similar to long ELPs regarding their capacity to undergo inverse temperature transition (ITT) behavior.

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“…For example, HPMA copolymerdoxorubicin conjugate (PK1, FCE28068) was the first of the series of synthetic polymer-anticancer drug conjugates developed in 1994 which entered clinical trial as anticancer agents (185,186). PK1 (MW 30kDa) containing 8.5%w/w doxorubicin consists of the anticancer anthracycline antibiotic doxorubicin attached to the HPMA copolymer backbone through tetrapeptide sequence glycylphenylalanylleucylglycine (GFLG) which is degradable by lysosimes (187). PK1 was reported to show remarkable stability as well as increased accumulation of doxorubicin in melanoma tumour (17 -70 folds) and decreased cardio-and bone marrow toxicity in animals compared to free doxorubicin.…”

Section: N-(2-hydroxypropyl)methacrylamide (Hpma)mentioning

confidence: 99%

Polymer-Drug Nanoconjugate – An Innovative Nanomedicine: Challenges and Recent Advancements in Rational Formulation Design for Effective Delivery of Poorly Soluble Drugs

Abioye

Chi-Tangyie²,

Kola-Mustapha³

et al. 2016

PNT

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Background: Over the last four decades, the use of water soluble polymers in rational formulation design has rapidly evolved into valuable drug delivery strategies to enhance the safety and therapeutic effectiveness of poorly soluble drugs, particularly anticancer drugs. Novel advances in polymer chemistry have provided new generations of well defined polymeric architectures for specific applications in polymer-drug conjugate design. However, total control of crucial parameters such as particle size, molecular weight distribution, polydispersity, localization of charges, hydrophilic-lipophilic balance and non site-specific coupling reactions during conjugation has been a serious challenge. Objective: This review briefly describes the current advances in polymer-drug nanoconjugate design and various challenges hindering their transformation into clinically useful medicines. Method: Existing literature was reviewed. Results: This review provides insights into the significant impact of covalent and non-covalent interactions between drug and polymer on drug loading (or conjugation) efficiency, conjugate stability, mechanism of drug release from the conjugate and biopharmaceutical properties of poorly soluble drugs. The utility values and application of Quality by Design principles in rational design, optimization and control of the Critical Quality Attributes (CQA) and Critical Process Parameters (CPP) that underpin the safety, quality and efficacy of the nanoconjugates are also presented. Conclusion: It was apparent that better understanding of the physicochemical properties of the nanoconjugates as well as the drug-polymer interaction during conjugation process is essential to be able to control the biodistribution, pharmacokinetics, therapeutic activity and toxicity of the nanoconjugates which will in turn enhance the prospect of successful transformation of these promising nanoconjugates into clinically useful nanomedicines.

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Preclinical evaluation of polymer-bound doxorubicin

Cited by 179 publications

References 27 publications

Phase II studies of polymer-doxorubicin (PK1, FCE28068) in the treatment of breast, lung and colorectal cancer

Phase II studies of polymer-doxorubicin (PK1, FCE28068) in the treatment of breast, lung and colorectal cancer

Elastin-like polypeptides and their applications in anticancer drug delivery systems: a review

Polymer-Drug Nanoconjugate – An Innovative Nanomedicine: Challenges and Recent Advancements in Rational Formulation Design for Effective Delivery of Poorly Soluble Drugs

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